Are You Confident of the Diagnosis?

What you should be alert for in the history

Trichothiodystrophy (TTD) is a rare genetic disease characterized by a spectrum of clinical features, ranging from only hair involvement to severe developmental and neurological abnormalities. Many clinicians regard TTD as a clinical and biochemical feature that may be found in a range of diseases, rather than as a disease in itself. In this chapter, TTD will be described as a single entity for simplification.

Most patients with TTD have brittle, sparse, dry, and easily broken scalp hair that is deficient in sulfur and cysteine content. Other ectodermal structures (skin, nails, and teeth) are often involved, leading many to consider TTD a form of ectodermal dysplasia.

Characteristic findings on physical examination

The skin of TTD patients may appear normal, but may demonstrate various forms of ichthyosis, hypohidrosis, eczematous changes, and increased photosensitivity, characterized by persistent erythroderma with minimal sun exposure.

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Many TTD patients also have nail findings, including but not limited to onychodystrophy, brittle nails, hypoplasia, koilonychia, onychoschizia (nail splitting), and ridging.

Teeth abnormalities include dental caries and enamel hypoplasia; dystrophic teeth may be present as well.

Because of the variability of clinical features, several acronyms have been created over time that serve as mnemonics for the major clinical features of the disease. The acronyms PIBIDS, IBIDS, and BIDS describe patients based on the presence or absence of the following features: photosensitivity (P), ichthyosis (I), brittle hair (B), intellectual impairment (I), decreased fertility (D), and short stature (S).

Other manifestations of TTD include mental and growth retardation, short stature, micrognathia, small nose, large ears, decreased fertility, ocular abnormalities such as congenital cataracts, bone abnormalities such as central osteosclerosis and peripheral osteopenia, and neurological findings such as ataxia, impaired motor control, and contractures. Despite myriad clinical features, most TTD patients are very sociable, outgoing and friendly individuals.

One large systemic review of 112 published cases of TTD found the most common clinical features were brittle hair or hair shaft abnormalities (96%), neurological abnormalities (86%), short stature (73%), ichthyosis (65%), abnormal characteristics at birth (53%), ocular abnormalities (51%), infections (46%), and photosensitivity (42%).

Studies have demonstrated that many TTD patients are born prematurely or are small for gestational age and are born from mothers whose pregnancies were complicated by preeclampsia or even HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome. Presumably, the latter contributes to the former. In addition, many TTD patients are born with a transient collodian membrane.

Expected results of diagnostic studies

The diagnosis of TTD is definitively made by a combination of a thorough history and physical exam, laboratory studies, including molecular genetic analysis, and imaging studies such as standard radiographs and computed tomography (CT) scans.

A clinical suspicion of TTD based on a history of hair loss, hair breakage, or poor growth, and a careful exam of the hair and scalp, warrants hair microscopy as a diagnostic next step. If hair microscopy reveals features consistent with TTD such as very short hairs, loss of cuticles, brush ends, trichorrhexis nodosa-like abnormalities, and trichoschisis, then the hair should be viewed under cross-polarized light microscopy.

The finding of a ’tiger-tail banding’ pattern of hair shafts (representing a pattern of light, alternating with dark bands), seen with polarized light microscopy is observed in greater than 90% of affected patients with TTD. Amino acid analysis should be performed on the hairs that demonstrate the ’tiger-tail banding’ pattern. A reduction in the cystine or methionine content of the hairs below two standard deviations is the gold standard for diagnosing TTD.

Abnormal laboratory findings in patients with TTD may include neutropenia, low IgM levels, an elevated hemoglobin A2, and anemia with a low mean corpuscular volume. Radiographic abnormalities include peripheral osteopenia and central osteosclerosis, while brain magnetic resonance imaging (MRI) scans may demonstrate hypomyelination of the white matter with enlarged ventricles in some patients as well as basal ganglia calcifications.

Diagnosis confirmation

Trichothiodystrophy is closely related to xeroderma pigmentosum (XP) and Cockayne syndrome (CS) because all three disease entities are characterized by defects in DNA excision repair. Therefore, the latter two entities should be on the differential in any patient suspected of having TTD.

Unlike patients with XP, TTD patients are not at an increased risk of developing skin cancer and do not develop pigmentary abnormalities.

CS is characterized by characteristic facial features (deep set eyes, prominent ears), short stature, pigmentary retinopathy, and sun sensitivity without an increased skin cancer risk.

Progressive sensorineural deafness is an early feature of both XP and CS, but not TTD, and may help distinguish the three.

Malnutrition and acrodermatitis enteropathica are two other disease entities that may share many similar features with TTD. It is important to consider these diagnoses as well because acrodermatitis enteropathica is completely correctable with diet.

Metabolic diseases such as argininosuccinate lyase deficiency and ornithine carboxylase deficiency can mimic TTD. Therefore, urinary amino acid analysis may need to be performed to rule out these genetic metabolic diseases.

Who is at Risk for Developing this Disease?

TTD is a rare genetic disease with a prevalence of approximately 1 per million in the United States and Europe, with males and females equally affected. While there are no documented risk factors for the development of TTD, approximately 1/3 of individuals were born from a pregnancy complicated by abnormalities such as preeclampsia or even HELLP syndrome.

Whether TTD as a disease complex is responsible for the pregnancy abnormalities is unclear; however, it is possible that some of the clinical features observed in patients with TTD may be attributed to maternal pregnancy abnormalities that compromise the fetus.

What is the Cause of the Disease?

TTD is an autosomal recessive disease caused by mutations in one of three DNA repair genes (XPB, XPD, or TTDA), or in TTDN1, a gene with unknown function(s).


The genes XPB, XPD, and TTDA are involved in nucleotide excision repair and basal transcription as part of the basal transcription factor IIH (TFIIH). It is postulated that the mutations in genes leading to TTD primarily affect transcription, whereas the mutations in these same genes that lead to XP primarily affect DNA repair. The laboratory findings of elevated Hemoglobin A2 and a low MCV (mimicking thalassemia) common to TTD patients support the transcriptional defect theory.

Systemic Implications and Complications

TTD patients are at an increased risk of developing repeated infections (of bacterial, viral or fungal origin), particularly in the respiratory tract, and this accounts for a large percentage of morbidity and mortality in this population. There is an approximate 20-fold increase in the probability of death in TTD children under 10 years of age, as compared to the US general population, mostly attributed to infections.

Infections of the ear, gastrointestinal tract, and urinary tract are also relatively frequent. As a result, TTD patients, on average, have a significantly shorter life span as compared to the general population.

The majority of TTD patients have some neurological abnormalities, ranging from developmental delay, intellectual impairment, and microcephaly to impaired motor control or psychomotor retardation. Importantly, these patients’ neurological conditions are nonprogressive.

TTD patients are also prone to develop cataracts and other ocular abnormalities (nystagmus, strabismus, myopia, etc.) at an early age, with some manifesting at birth. If undetected, ocular abnormalities can lead to vision impairment and early childhood developmental and learning abnormalities.

For unknown reasons, TTD patients are particularly prone to dental caries. Therefore, they require meticulous dental care.

Although TTD and XP share defects in the XPB and XPD genes, TTD patients are not at a significantly increased risk for skin cancer, even though they are extremely photosensitive and can develop a severe sunburn with minor sun exposure.

Other systemic complications of TTD may include decreased fertility (from gonadal dysgenesis), bone abnormalities, contractures, cardiomyopathy and anemia.

Mothers of TTD patients are at a significantly increased risk of developing preeclampsia or HELLP syndrome in future pregnancies, particularly if they have developed these complications in previous pregnancies. Therefore, subsequent pregnancies must be followed very closely for the development of these potentially life-threatening complications.

Treatment Options

Treatment options are summarized in Table I.

Table I.
Systemic Complication Management Strategy
Alopecia/brittle hair Conservative hair dressing: avoid curling irons, curlers, straighteners, hair dryers on high heat, or excessive amounts of hair products. Wash hair gently. Use conditioner on a routine basis.
Contractures Braces and walkers to help with ambulation. Routine physical therapy to preserve range of motion. Tendon release surgery in severe cases.
Dental caries Routine dental exams. Strict dental hygiene.
Ichthyosis Frequent application of moisturizers (especially ones containing urea, lactic acid). Exfoliation with products containing alpha-hydroxy acids. Topical, or even oral, retinoids in severe cases.
Infections (respiratory, ear, urinary, gastrointestinal) Early recognition and treatment to prevent complications. IVIG in patients with hypogammaglobulinemia.
Neurological impairments Neurology exams on an annual basis
Ocular abnormalities (cataracts, stabismus, nystagmus) Close follow-up and routine annual exams with opthalmology, beginning at birth
Photosensitivity Avoidance of sun exposure, wearing protective clothing, generous use of sunscreen products
Hypogammaglobulinemia IVIG – intravenous immunoglobulin

Optimal Therapeutic Approach for this Disease

There is currently no cure for TTD.

Management of TTD involves participation from many specialties of medicine, including but not limited to dermatology, neonatology, pediatrics, ophthalmology, neurology, dentistry, infectious disease, genetics, hematology, and immunology. Efforts should be focused on early detection and prevention of known complications (see Table I).

Because infections account for significant morbidity and mortality, any sign of an infection should be taken seriously and treated aggressively. Respiratory, gastrointestinal, urinary, and ear infections account for the majority of cases. Patients also are prone to developing severe dental caries and should therefore have routine dental exams.

Although most TTD patients do not have an underlying immunodeficiency, there are case reports of patients with hypogammaglobulinemia. In such cases, the patients benefited from intravenous immunoglobulins.

A large number of TTD patients suffer from ichthyosis and benefit from routine moisturization and exfoliation (particularly with products that contain urea or lactic acid for moisturization, and products containing alpha-hydroxy acids for exfoliation). In severe cases of ichthyosis, topical retinoids, or even oral retinoids, can help reduce scaling.

Although no specific doses have been specified in clinical trials for this unique patient population, presumably, the management of the ichthyosis is similar to the management of icthyosis in other conditions. The goal of treatment is to prevent drying, cracking and splitting of the skin, which may predispose to secondary skin infections.

Because TTD patients are particularly photosensitive, adequate sun protection is necessary, in the form of both protective clothing and application of sunscreens.

While brittle hair, sparse hair, or alopecia are not life-threatening conditions, their effect on a patient’s psyche can be substantial. Encourage patients to take a conservative approach to hair dressing. They should avoid styling tools such as curling irons, straighteners, hair dryers on high heat and excessive amounts of hair products. Applying a conditioner on a routine basis and washing hair gently are important measures to prevent traumatic injury to hair.

TTD patients frequently have ocular abnormalities; approximately two-thirds of these patients suffer from cataracts. Some patients are even born with cataracts. Therefore, these patients should be routinely followed by ophthalmologists, starting from birth.

Patients who have motor impairments or who develop contractures should utilize braces and/or walkers to help ambulate. A routine physical therapy program should be instituted to promote range of motion. Tendon release surgery may be considered in severe cases of contractures.

Patient Management

Explain to patients and their families that TTD is a genetic disease with a spectrum of clinical features. Teach patients about the different abnormalities associated with TTD. Genetic counseling should be provided to all families affected by the disease, particularly those considering having children. Because prenatal diagnosis is possible, future pregnancies can be screened.

Patients should learn to recognize the signs of infection (fever, malaise, chills, productive cough, and rhinorrhea) and to seek treatment as quickly as possible. Remind patients to keep their immunizations up to date, including annual influenza shots for all patients, and pneumococcal vaccine for the appropriate age groups.

TTD patients are particularly prone to sun sensitivity and should be advised to use sun protection at all times. Minimizing sun exposure and using a combination of sunscreen and protective clothing, including hats, when exposed to the sun are reasonable strategies.

Patients suffering from ichthyosis should be taught to keep their skin moisturized to prevent secondary infections. Specifically, encourage patients to apply moisturizers immediately after a shower or bath to retain a maximum amount of moisture. Creams or ointments containing urea or lactic acid are particularly effective for moisturization. Products with alpha-hydroxy acids such as glycolic acid can help control excessive scaling.

Encourage patients to take a conservative approach to hair dressing (avoid styling tools such as curling irons, straighteners, or hair dryers on high heat). Patients should also use hair products judiciously, as chemicals in the products can further damage already brittle hair. Encourage patients to gently wash their hair to prevent unnecessary trauma, and to use a conditioner on a routine basis to help alleviate brittleness.

Encourage patients to routinely follow-up with their dentists and ophthalmologists because TTD patients are more prone to develop dental abnormalities (particularly severe dental caries) and ocular abnormalities (such as cataracts, nystagmus, and strabismus). Patients should be encouraged to maintain meticulous dental hygiene.

A physical therapy program should be instituted to promote and sustain range of motion and balance, particularly for patients with impaired motor control and contractures.

Unusual Clinical Scenarios to Consider in Patient Management

TTD, XP and CS share mutations in similar DNA repair genes. It is therefore not surprising that patients may present with an overlap syndrome that has clinical features consistent with one or more of these aforementioned diseases.

What is the Evidence?

Cheng, S, Stone, J, de Berker, D. “Trichothiodystrophy and fragile hair: the distinction between diagnostic signs and diagnostic labels in childhood hair disease”. Br J Dermatol. vol. 161. 2009. pp. 1379-83. (Amino acid analysis was performed on hair samples from twenty-five patients with hair fragility and clinical characteristics suspicious for TTD. The study demonstrated that only rarely is clinically fragile hair associated with a diagnosis of TTD. The ’tiger-tail change’ that is often associated with TTD is a sensitive but not specific marker of TTD.)

Faghri, S, Tamura, D, Kraemer, K, DiGiovanna, J. “Trichothiodystrophy: a systemic review of 112 published cases characterizes a wide spectrum of clinical manifestations”. J Med Genet. vol. 45. 2008. pp. 609-21. (This is an excellent comprehensive review of a large number of published cases of TTD, detailing the common to rare clinical features of the disease.)

Kraemer, K, Patronas, N, Schiffmann, R, Brooks, B, Tamura, D, DiGiovanna, J. “Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship”. Neuroscience. vol. 145. 2007. pp. 1388-96. (A discussion and comparison of XP, TTD, and CS is presented with a focus on the neurological complications of the diseases.)

Liang, C, Morris, A, Schlucker, S, Imoto, K, Price, V, Menefee, E. “Structural and molecular hair abnormalities in trichothiodystrophy”. J Invest Dermatol. vol. 126. 2006. pp. 2210-16. (This article provides an excellent overview of the hair of TTD patients. The hairs of fifteen patients with TTD were analyzed for structural and molecular abnormalities. No association was found between clinical disease severity and the percentage of abnormal hairs.)

Morice-Picard, F, Cario-Andre, M, Rezvani, H, Lacombe, D, Sarasin, A, Taieb, A. “New clinico-genetic classification of trichothiodystrophy”. Am J Med Genet. vol. 149A. 2009. pp. 2020-30. (The authors in this study examined eighty-eight patients with TTD, searching for a correlation between genotype and phenotype. They found that patients with the TFIIH mutation are more likely to have congenital ichthyosis and a collodion membrane at birth. On the other hand, patients with the TTDN1 mutation are more likely to be nonphotosensitive, but are also more likely to have hypogonadism.)

Xiaolong, Z, Khan, S, Tamura, D, Patronas, N, Zein, W, Brooks, B. “Brittle hair, developmental delay, neurologic abnormalities, and photosensitivity in a 4-year old girl”. J Am Acad Dermatol. vol. 63. 2010. pp. 323-8. (A case of TTD from dermatology grand rounds at the National Institutes of Health, with an excellent discussion of the salient features of TTD)